Thermal (functional) imaging can show anatomically relevant information that is useful in assessing local and regional function of the neuronal network. Performing regional analysis of the effects of cold provocation on the body is important in the evaluation of diabetic peripheral neuropathy. A thermal image video presents information about the components that contribute to the bioheat transfer for a particular region affected by damaged neurons in that region of the body. When cold challenged, the thermal pattern of the toes and plantar regions of the foot and hands will reveal a spatial and temporal depiction of the neuronal function/activity of the foot or hand as it modifies the thermoregulatory system when imaged in the infrared wavelengths. The thermal images obtained contain information not currently analyzed for a relationship of these parameters (spatial and temporal) that correlate to the risk of onset, or increase in, the level of peripheral neuropathy.
U.S. Pat. No. 5,678,566 to Dribbon, describes the potential of infrared (thermal) imaging as a diagnostic tool for diabetic foot (peripheral neuropathy). Prior patents measure visual patterns of infrared thermal emissions from various regions of the body employing thermochromic liquid crystal technology (TLC) (See U.S. Pat. No. 5,124,819 to Davis, U.S. Pat. No. 5,678,566 to Dribbon, U.S. Pat. No. 4,327,742 to Meyers et. al., and U.S. Pat. No. 4,327,743 to Katz). TLC technology comes with a number of inherent limiting factors. Microencapsulation process is often used to reduce the degradation of pure TLC materials, which are organic compounds that easily degrade when exposed to chemical contamination and to ultraviolet (UV) light. Additionally, before the TLC can be used for the temperature measurement, a hue-temperature calibration must be conducted. This calibration must be repeated frequently.
It is well known that the lighting angle and the coating thickness significantly affects the TLC hue-temperature calibration curves, and a complete understanding on how the temperature measurement uncertainty of the TLC is influenced by those factors is a significant limitation.
Prior disclosures have failed to optimize the device so that (i) the temporal and spatial temperature changes represented by color changes would be readily quantifiable nor the processed data readily presented to the medical technician or physician; (ii) the design of the system would facilitate its use as a tool for contra-lateral comparison and visual examination by the foot care specialist in a diabetic foot screening environment; and (iii) these past systems have not presented a means or analytical technique to quantify the level of risk of a asymptomatic diabetic patient.
These prior devices and techniques used to obtain thermal, infrared emission measurements were not designed specifically for risk stratification of diabetic patients who present without symptoms of loss of neuronal function as a precursor to peripheral neuropathy. These prior devises fail to present a model for interpreting the results of the thermal measurements. These prior devices fail to combine new thermal detectors with a clinical procedure for stimulating homeostasis and measuring the related neuronal function.
A number of research papers have been presented on various aspects of use of LCT technology for peripheral neuropathy. See Bharara et al.: “Thermoography and Thermometry in the Assessment of Diabetic Foot: A Case for Furthering the Role of Thermal Techniques,” Lower Extremity Wounds 5(4); 2006, 250-260; Bharara et al.: “Cold Emersion Recovery Responses in the Diabetic Foot with Neuropathy,” International Wound Journal, 2008, 5:562-569; Stess et al.: “Use of Liquid Crystal Thermography in the Evaluation of the Diabetic Foot,” Diabetes Care., 9(3):267-272 (May-June, 1986); Benbow et al.: “The Prediction of Diabetic Neuropathic Plantar Foot Ulceration by Liquid-Crystal Contact Thermography,” Diabetes Care, 17(8)835-639 (August, 1994). These papers and others limit their discussion to LCT. They measure static conditions and not dynamic, functional signals. They describe signals from advanced conditions when a patient has already developed peripheral neuropathy.
According to the Center for Disease Control (CDC), diabetes afflicts an estimated 171 million people worldwide, including more than 24 million Americans. Diabetic patients are at risk for a wide array of complications including heart disease, kidney disease (nephropathy), ocular diseases (diabetic retinopathy), and peripheral neuropathy (diabetic foot).
It is estimated that 60-70% of diabetics have some degree of neuropathy. Fifteen percent, two million, of these will develop a foot ulcer during their lifetime. Foot ulcers are the main cause, 85%, of lower extremity amputation in patients with diabetes. Neuropathy is one cause for the impairment thermoregulatory function including bioheat production by metabolic processes in the diabetic foot. Patients with long-standing neuropathy will have poor regulatory mechanisms and hence altered microcirculatory dysfunction. This condition is linked to neuropathic complications that alter the regulatory mechanisms controlling heat production in the peripheral neuropathy.
82,000 amputations are performed annually on diabetics. Studies have shown that about 5% of diabetic patients will develop a foot ulcer in a given year. Fifteen percent of diabetics will undergo amputation sometime in their lives. Foot pathology accounts for 25% of all hospital stays among people with diabetes, and the cost of foot disorder diagnosis and management are estimated at $10.9 billion dollars annually.
Economically, treatment and other costs attributable to peripheral neuropathy would be reduced significantly if the U.S. population of diabetics were screened, preclinical signs of peripheral neuropathy were identified, and these individuals would undergo educational intervention. Identification of the “at risk” foot prior to the onset of altered foot anatomy or clinically significant peripheral vascular disease will allow for the institution of preventative measures and vigilant surveillance that may alter the natural history of this most-feared complication of diabetes and save millions of dollars in annual healthcare costs.
It is recommended that all patients with diabetes have a thorough pedal examination at least once a year, even if no signs of neuropathy are present. Clinical testing may include a number of tests, some of which present inter- and intra-observer variability, such as vibration sensation applied by a tuning fork test or pressure sensitivity as applied by a monofilament test. Others are expensive or are invasive such as the ankle brachial index, transcutaneous oxygen measurements, pulse volume recordings, laser Doppler flowmetry and/or nerve conduction tests. As a result, longitudinal assessment of progression or treatment (therapeutics) it is nearly impossible except where significant changes occur. Today an instrument that gives a preclinical indication of risk for onset of neuropathy is not available.
One function of the neuronal system is the control of capillaries as a means for thermoregulation to maintain body temperature through heat exchange processes. The capillary flow is controlled by thermoreceptor signals that trigger the vasodilatory response in the skin. This is an auto-regulatory mechanism triggered by thermal stress. Dysfunction of this process can signal the presence of peripheral neuropathy. Cold and warm receptors are located at a depth of tenths of millimeters and are activated with changes in surface temperature, which are easily visible as far infrared i.e., thermal, emission.
Oxidative stress has been associated with the pathogenesis of many diseases, including diabetes and cardiovascular disease. This state is caused by an imbalance of oxidants and antioxidants, wherein the body can no longer repair damage from naturally occurring by-products of oxidation, such as free radicals. Endothelial cells are among the structures damaged, affecting the production of endothelium-induced nitric oxide (eNOS), a signaling molecule essential to proper regulation of the vasculature. To compensate, the body will produce inducible nitric oxide (iNOS). However, iNOS produced in an oxidative environment will combine with the free radical superoxide to produce high levels of peroxynitrite, moving the body into a state of nitrosative stress. Sustained nitrosative stress can lead to peripheral nerve damage and, eventually, nerve death.
Depending on its severity, nerve damage can manifest as a hypothermic or hyperthermic area on an infrared image. Both endothelial dysfunction and peripheral nerve damage have been associated with vasoconstriction, which would produce hypothermic areas in an infrared image. As damage to the sympathetic nervous system progresses, these areas will begin to appear hyperthermic, as chronic inflammation is associated with irreversible nerve damage and impending cell death.
Although thermal imaging has been used for structural imaging of the diabetic foot, these studies have focused only on discovering absolute skin/tissue temperature differences between individuals. Investigators hypothesized that differential spatial temperature characteristics in affected regions of the body were early indications of peripheral neuropathy, and they hoped that abnormal capillary function in the affected regions could be detected. The significance and value of this approach to diagnosing or staging peripheral neuropathy has come into question by a number of investigators.
Bharara, et al. studied cold immersion recovery response for diabetics with peripheral neuropathy. Bharara, et al. describe a very different thermal measurement device based on thermochromic liquid crystals (TLC). The Bharara system is inherently limited and not able to measure temporal fluctuations at rates of greater than about 1 Hz. TLCs are not thermal imagers in the sense of infrared devices. These are liquid crystals that change color as a function of temperature and must be interpreted off-line. Lack of temperature precision is due to the need for the interpretation of the color displayed. TLC technology was appropriate to meet Bharara's goal for only measuring an initial temperature and a recovery temperature. Rapid measurements over an extended period of time is not feasible with TLC technology nor contemplated by Bharara.
Infrared imaging is a modality that has been misrepresented in the popular imagining. For example, if one were to point an infrared camera through a window at a bright sunny scene outside, the result would be a black featureless image. Window glass absorbs all infrared light and transmits none. The color of an object to our eye is uncorrelated to its infrared color (emissivity and temperature). Factors that may affect other measurement approaches, such as tissue thickness and pigmentation, are not major contributors to the measured thermal emission.
Memarian et al., state, “thermography is skin color invariant since there is no difference in emissivity between black, white and burnt skin, in vivo or in vitro. Human skin has an emissivity of about 0.98. Thermal radiation from the skin originates in the epidermis and is independent of race; it depends therefore only on the surface temperature. Secondly, thermal image quality is independent of ambient lighting conditions and can thus be effective both night and day.” As explained above, skin pigmentation is not the dominant term in thermal emission. The energy radiated by a blackbody radiator per second per unit area is given by εσT4 where ε is the emissivity (0.98 for human tissue), σ is the Stefan-Boltzman constant (5.6703×10−6 watts/m2K4), and the temperature, T, is in degrees Kelvin. ε is a linear factor in the thermal emission, while temperature is to the fourth power. From the Stefan-Boltzman relationship, the small variation in ε due to pigmentation is not a major contributor to the measured thermal emission.
The normal body core temperature stays at a constant 37° C. or about 310° K. FIG. 1 shows the radiative emittance for a black body (emissivity=1) for the typical human skin regardless of race. Note that the emissivity is at a near maximum in the far infrared (8 to 12 micrometers).
Tissue thickness values of about 11.05, 7.85, 6.65, 6.55, and 5.05 mm for metatarsal heads 1 through 5, respectively, have been reported. The signal that is observed is dominated by the heat transfer from the capillaries to the surrounding plantar tissue. That capillary bed is found between about 0.6 and about 1.0 mm from the surface of the skin (see FIG. 2, element 1). Both visible and infrared signals can measure changes in the microvascular function at this depth.
The passive thermoregulatory system is modeled using the Pennes bioheat equation. Pennes' bioheat equation is based on the regular heat diffusion equation but where an additional isotropic source term has been added to account for the heat transported by blood in the surrounding tissues. The Pennes bioheat equation is given by
                    ∇                  ·          k                    ⁢              ∇        T              +                  ρ        bl            ⁢              w        bl            ⁢                        c          bl                ⁡                  (                                    T                              bl                ,                a                                      -            T                    )                      +          q      m        =      ρc    ⁢                  ∂        T                    ∂        t            where k is the thermal conductivity of the tissue, T is the temperature of the tissue, ρbl is the blood density, wbl is the volumetric rate of blood perfusion to the tissue per unit volume, cbl is the blood specific heat, Tbl, is the arterial blood temperature of the tissue, qm is the rate of metabolic heat production per unit volume, ρ is the tissue density, c is the tissue specific heat, and t is time. The perfusion heat source term assumes that all the heat transfer to the tissue takes place a few millimeters from the skin surface within the capillary bed.
This heat transfer equation does not require explicit knowledge of the blood perfusion, nor blood flow. Therefore, the infrared measurements showing changes in radiative emission of the skin surface can be deduced to be a result of the auto-thermoregulation instigated by the functional integrity of the neuronal network.